This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. CXCR4 chemokine receptors are found on the surface of immune cells, and together with their specific natural ligand, play a role in a number of disease states. CXCR4 has involvement in cancer progression and metastasis, and the development of rheumatoid arthritis. Within the last ten years the CXCR4 has been revealed as the entry route for some HIV strains into cells, generating interest in a new therapeutic approach to treatment via entry inhibitor drugs rather than the current preference for reverse transcriptase and protease inhibitors. Our aim is to develop new inhibitors for the CXCR4 co-receptor. They are rigid macrocyclic compounds and their transition metal complexes based on a known CXCR4 inhibitor that has been clinically tested for anti-HIV efficacy as well as its utility in facilitating stem cell transplantation. The rigidification we have implemented should lead to improved CXCR4 binding, as well as illuminating the structural requirements for binding transition metal complexes to this important receptor. We have already demonstrated the utility of our synthetic schemes by successfully producing the initial target molecules for both of our proposed types of rigidification. These lead compounds have also been screened for CXCR4 binding using flow cytometry methods to quantify the inhibition of known CXCR4-binding antibodies by in immune cells which overexpress the CXCR4 receptor. We look forward to completing the synthesis and testing of a series of related compounds to gain further insights into the essential design features for this drug class through spectroscopic and biological studies.